Flaviviridae
The Flaviviridae is a group of positive single-stranded RNA viruses with a genome size from 9-15 kb. They are enveloped viruses of approximately 40-50 nm. An overview of the Flaviviridae taxonomy is available from the International Committee for Taxonomy of Viruses. The Flaviviridae consists of three genera.                1. Flaviviruses. This genus includes the Dengue virus group (Dengue virus, Dengue virus type 1, Dengue virus type 2, Dengue virus type 3, Dengue virus type 4), the Japanese encephalitis virus group (Alfuy Virus, Japanese encephalitis virus, Kookaburra virus, Koutango virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Stratford virus, Usutu virus, West Nile Virus), the Modoc virus group, the Rio Bravo virus group (Apoi virus, Rio Brovo virus, Saboya virus), the Ntaya virus group, the Tick-Borne encephalitis group (tick born encephalitis virus), the Tyuleniy virus group, Uganda S virus group and the Yellow Fever virus group. Apart from these major groups, there are some additional Flaviviruses that are unclassified.        2. Hepaciviruses. This genus contains only one species, the Hepatitis C virus (HCV), which is composed of many clades, types and subtypes.        3. Pestiviruses. This genus includes Bovine Viral Diarrhea Virus-2 (BVDV-2), Pestivirus type 1 (including BVDV), Pestivirus type 2 (including Hog Cholera Virus) and Pestivirus type 3 (including Border Disease Virus).        
One of the most important Flaviviridae infections in humans is caused by the hepatitis C virus (HCV). This is the second major cause of viral hepatitis, with an estimated 170 million carriers world-wide (World Health Organization; Hepatitis C: global prevalence, Weekly Epidemiological Record, 1997, 72, 341), 3.9 million of whom reside in the United States (Centers for Disease Control; unpublished data, http://www.cdc.gov/ncidod/diseases/hepatitis/heptab3.htm).
The genomic organization of the Flaviviridae share many common features. The hepatitis C virus (HCV) genome is often used as a model. HCV is a small, enveloped virus with a positive single-stranded RNA genome of ˜9.6 kb within the nucleocapsid. The genome contains a single open reading frame (ORF) encoding a polyprotein of just over 3,000 amino acids, which is cleaved to generate the mature structural and nonstructural viral proteins. The ORF is flanked by 5′ and 3′ non-translated regions (NTRs) of a few hundred nucleotides in length, which are important for RNA translation and replication. The translated polyprotein contains the structural core (C) and envelope proteins (E1, E2, p7) at the N-terminus, followed by the nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B). The mature structural proteins are generated via cleavage by the host signal peptidase (see: Hijikata, M. et al. Proc. Nat. Acad. Sci., USA, 1991, 88, 5547; Hussy, P. et al. Virology, 1996, 224, 93; Lin, C. et al. J. Virol., 1994, 68, 5063; Mizushima, H. et al. J. Virol., 1994, 68, 2731; Mizushima, H. et al. J. Virol., 1994, 68, 6215; Santolini, E. et al. J. Virol, 1994, 68, 3631; Selby, M. J. et al. Virology, 1994, 204, 114; and Grakoui, A. et al., Proc. Nat. Acad. Sci., USA, 1993, 90, 10538). The junction between NS2 and NS3 is autocatalytically cleaved by the NS2/NS3 protease (see: Hijikata, M. et al. J. Virol., 1993, 67, 4665 and Bartenschlager, R. et al. J. Virol., 1994, 68, 5045), while the remaining four junctions are cleaved by the N-terminal serine protease domain of NS3 complexed with NS4A. (see: Failla, C. et al. J. Virol., 1994, 68, 3753; Lin, C. et al. J. Virol., 1994, 68, 8147; Tanji, Y. et al. J. Virol., 1995, 69, 1575 and Tai, C. L. et al. J. Virol., 1996, 70, 8477) The NS3 protein also contains the NTP-dependent helicase activity which unwinds duplex RNA during replication. The NS5B protein possesses RNA-dependent RNA polymerase (RDRP) activity (see: Behrens, S. E. et al. EMBO J., 1996, 15, 12; Lohmann, V. et al. J. Virol., 1997, 71, 8416-8428 and Lohmann, V. et al. Virology, 1998, 249, 108), which is essential for viral replication. (Ferrari, E. et al. J. Virol., 1999, 73, 1649) It is emphasized here that, unlike HBV or HIV, no DNA is involved in the replication of HCV. Recently in vitro experiments using NS5B, substrate specificity for HCV-RDRP was studied using guanosine 5′-monophosphate (GMP), 5′-diphosphate (GDP), 5′-triphosphate (GTP) and the 5′-triphosphate of 2′-deoxy and 2′,3′-dideoxy guanosine (dGTP and ddGTP, respectively). The authors claimed that HCV-RDRP has a strict specificity for ribonucleoside 5′-triphosphates and requires the 2′- and 3′-OH groups. (Lohmann; Virology, 108) Their experiments suggest that the presence of 2′- and 3′-substituents would be the prerequisite for nucleoside 5′-triphosphates to interact with HCV-RDRP and to act as substrates or inhibitors.
Examples of antiviral agents that have been identified as active against the hepatitis C flavivirus include:                1. Interferon and ribavirin (Battaglia, A. M. et al. Ann. Pharmacother. 2000, 34, 487; Berenguer, M. et al. Antivir. Ther. 1998, 3 (Suppl. 3), 125);        2. Substrate-based NS3 protease inhibitors (Attwood et al. PCT WO 98/22496, 1998; Attwood et al. Antiviral Chemistry and Chemotherapy 1999, 10, 259; Attwood et al. German Patent Publication DE 19914474; Tung et al. PCT WO 98/17679), including alphaketoamides and hydrazinoureas, and inhibitors that terminate in an electrophile such as a boronic acid or phosphonate (Llinas-Brunet et. al. PCT WO 99/07734);        3. Non-substrate-based inhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al., Biochemical and Biophysical Research Communications, 1997, 238, 643 and Sudo K. et al. Antiviral Chemistry and Chemotherapy 1998, 9, 186), including RD3-4082 and RD3-4078, the former substituted on the amide with a 14 carbon chain and the latter processing a para-phenoxyphenyl group;        4. Thiazolidine derivatives which show relevant inhibition in a reverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al. Antiviral Research 1996, 32, 9), especially compound RD-1-6250, possessing a fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193;        5. Thiazolidines and benzanilides identified in Kakiuchi N. et al. J. EBS Letters 421, 217 and Takeshita N. et al. Analytical Biochemistry 1997, 247, 242;        6. A phenanthrenequinone possessing activity against HCV protease in a SDS-PAGE and autoradiography assay isolated from the fermentation culture broth of Streptomyces sp., Sch 68631 (Chu M. et al. Tetrahedron Letters 1996, 37, 7229), and Sch 351633, isolated from the fungus Penicillium griscofuluum, which demonstrates activity in a scintillation proximity assay (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9, 1949);        7. Selective NS3 inhibitors based on the macromolecule elgin c, isolated from leech (Qasim M. A. et al. Biochemistry 1997, 36, 1598);        8. HCV helicase inhibitors (Diana G. D. et al., U.S. Pat. No. 5,633,358 and Diana G. D. et al. PCT WO 97/36554);        9. HCV polymerase inhibitors such as nucleotide analogues, gliotoxin (Ferrari R. et al. Journal of Virology 1999, 73, 1649), and the natural product cerulenin (Lohmann V. et al. Virology 1998, 249, 108);        10. Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to at least a portion of a sequence of the HCV (Anderson et al. U.S. Pat. No. 6,174,868), and in particular the sequence stretches in the 5′ non-coding region (NCR) (Alt M. et al. Hepatology 1995, 22, 707), or nucleotides 326-348 comprising the 3′ end of the NCR and nucleotides 371-388 located in the core coding region of the HCV RNA (Alt M. et al. Archives of Virology 1997, 142, 589 and Galderisi U. et al., Journal of Cellular Physiology 1999, 81:2151);        11. Inhibitors of IRES-dependent translation (Ikeda N et al., Japanese Patent Pub. JP-08268890; Kai Y. et al. Japanese Patent Publication JP-10101591);        12. Nuclease-resistant ribozymes (Maccjak D. J. et al., Hepatology 1999, 30, abstract 995);        13. Amantadine, such as rimantadine (Smith, Abstract from Annual Meeting of the American Gastoenterological Association and AASLD, 1996);        14. Quinolones, such as ofloxacin, ciprofloxacin and levofloxacin (AASLD Abstracts, Hepatology, October 1994, Program Issue, 20 (4), pt. 2, abstract no. 293);        15. Nucleoside analogs (Ismaili et al. WO 01/60315; Storer WO 01/32153), including 2′-deoxy-L-nucleosides (Watanabe et al. WO 01/34618), and 1-(β-L-ribofuranosyl)-1,2,4-tri azole-3-carboxamide (Levovirin™) (Tam WO 01/46212); and        16. Other miscellaneous compounds including 1-amino-alkylcyclohexanes (Gold et al. U.S. Pat. No. 6,034,134), alkyl lipids (Chojkier et al. U.S. Pat. No. 5,922,757), vitamin E and other antioxidants (Chojkier et al. U.S. Pat. No. 5,922,757), squalene, bile acids (Ozeki et al. U.S. Pat. No. 5,846,964), N-(phosphonoacetyl)-L-aspartic acid, (Diana et al. U.S. Pat. No. 5,830,905), benzenedicarboxamides (Diana et al. U.S. Pat. No. 5,633,388), polyadenylic acid derivatives (Wang et al. U.S. Pat. No. 5,496,546), 2′,3′-dideoxyinosine (Yarchoan et al. U.S. Pat. No. 5,026,687), benzimidazoles (Colacino et al. U.S. Pat. No. 5,891,874), glucamines (Mueller et al. WO 01/08672), substituted-1,5-imino-D-glucitol compounds (Mueller et al. WO 00/47198).Orthomyxoviridae        
The Orthomyxoviridae is a group of segmented negative single-stranded RNA viruses with a genome size from 10-13.6 kb. They are enveloped viruses of approximately 80-120 nm. An overview of the Orthomyxoviridae taxonomy is available from the International Committee for Taxonomy of Viruses. The Orthomyxoviridae consists of three genera, which can be distinguished on the basis of antigenic differences between their nucleocapsid (NP) and matrix proteins (M).                1. Influenzavirus A, B. This genus contains influenza A and B viruses each of which contain eight distinct RNA segments. Influenza B viruses show little variability in their surface glycoproteins and only infect humans. On the other hand, influenza A viruses have great variability in their surface glycoproteins of influenza A viruses, and they can be divided into subtypes based on the antigenic nature of their hemagglutinin (HA) and neuroamidase (NA) glycoproteins and infect humans as well as swine, horses, seals, fowl, ducks and many other species of birds.        2. Influenzavirus C. This genus contains only one species, influenza C, which contains only seven distinct RNA segments. Influenza C only has a single multifunctional glycoprotein and infects mainly humans, but has also been isolated from swine in China.        3. Influenzavirus D. This genus contains influenza D, which is solely tick-borne viruses that are structurally and genetically similar to influenza A, B and C.        
One of the most important Orthomyxoviridae infections in humans is caused by the influenza A virus. These viruses are highly contagious and cause acute respiratory illness that has plagued society in epidemic proportions since ancient times. One of the earliest recordings of an influenza A epidemic can be traced to Hippocrates in 412 BC. These epidemics are rather frequent and are often fatal to the elderly, however these epidemics are quite unpredictable. These viruses are unique respiratory tract viruses, in that they undergo significant antigenic variation. Both hemagglutinin (HA) and neuroamidase (NA) glycoproteins are capable of antigenic drifts and shifts. There are fourteen known hemagglutinin (H1-H14) glycoproteins and nine known neuroamidase (N1-N9) glycoproteins. For example, since the first human influenza virus was isolated in 1933, major antigenic shifts have occurred. In 1957, the H2N2 subtype (Asian influenza) replaced the H1N1 subtype (Spanish influenza). Currently, the primary subtypes of influenza are H1N1, which reappeared in 1977 and H3N2, which reappeared in 1968.
The vast majority of research on influenza virus gene expression and RNA replication has been carried out with the influenza A virus. The most striking feature of the influenza A virion is a layer of about 500 spikes radiating outward (10 to 14 nm) from the lipid envelope. These spikes are of two types: rod-shaped spikes of HA and mushroom-shaped spikes of NA. The ratio of HA and NA varies, but is usually 4-5 to 1. Each gene segment encodes its own proteins, with the exception of the seventh and eighth, which encodes M1 and M2, and NS1 and NS2 respectively. The first 12 nucleotides at the 3′-end and the first 13 nucleotides at the 5′-end of each vRNA segment are conserved in all eight RNA segments. The first gene to have its nucleotide sequence determined was HA. Since then, all 14 known HA antigenic subtypes and many variants within the subtypes have been determined.
In infected cells, the vRNAs are both transcribed into mRNAs and replicated. The synthesis of mRNA is distinct, in that the RNA is primed by 5′ capped fragments derived from newly synthesized host-cell RNA polymerase II transcripts. The mRNA chain elongates until a stretch of uridine residues is reached 15-22 nucleotides before the 5′-ends of the vRNAs where transcription ends and polyadenylate is added to the mRNAs. For replication to occur, an alternative type of transcription is required that results in the production of full-length copies of the vRNAs. The full-length transcripts are initiated without a primer and are not terminated at the poly(A) site used during mRNA synthesis. The second step in replication is the copying of the template RNAs into vRNAs. This synthesis also occurs without a primer, since the vRNAs contain 5′-triphosphorylated ends. All three types of virus-specific RNAs mRNA, template RNA and vRNA—are synthesized in the nucleus.
Examples of antiviral agents that have been identified as active against the influenza A virus include:                1. Actinomycin D (Barry, R. D. et al. “Participation of deoxyribonucleic acid in the multiplication of influenza virus” Nature, 1962, 194, 1139-1140);        2. Amantadine (Van Voris, L. P. et al. “Antivirals for the chemoprophylaxis and treatment of influenza” Semin Respir Infect, 1992, 7, 61-70);        3. 4-Amino- or 4-guanidino-2-deoxy-2,3-didehydro-D-N-acetylneuroaminic acid-4-amino- or 4-guanidino-Neu 5 Ac2en (von Itzstein, M. et al. “Rational design of potent sialidase-based inhibitors of influenza virus replication” Nature, 1993, 363, 418-423);        4. Ribavirin (Van Voris, L. P. et al. “Antivirals for the chemoprophylaxis and treatment of influenza” Semin Respir Infect, 1992, 7, 61-70);        5. Interferon (Came, P. E. et al. “Antiviral activity of an interferon-inducing synthetic polymer” Proc Soc Exp Biol Med, 1969, 131, 443-446; Gerone, P. J. et al. “Inhibition of respiratory virus infections of mice with aeresols of synthetic double-stranded ribonucleic acid” Infect Immun, 1971, 3, 323-327; Takano, K. et al. “Passive interferon protection in mouse influenza” J Infect Dis, 1991, 164, 969-972);        6. Inactivated influenza A and B virus vaccines (“Clinical studies on influenza vaccine—1978” Rev Infect Dis, 1983, 5, 721-764; Galasso, G. T. et al. “Clinical studies on influenza vaccine—1976” J Infect Dis, 1977, 136 (suppl), S341-S746; Jennings, R. et al. “Responses of volunteers to inactivated influenza virus vaccines” J Hyg, 1981, 86, 1-16; Kilbourne, E. D. “Inactivated influenza vaccine” In: Plothin S A, Mortimer E A, eds. Vaccines Philadelphia: Saunders, 1988, 420-434; Meyer, H. M., Jr. et al. “Review of existion vaccines for influenza” Am J Clin Pathol, 1978, 70, 146-152; “Mortality and Morbidity Weekly Report. Prevention and control of Influenza: Part I, Vaccines. Recommendations of the Advisory Committee on Immunication Practices (ACIP)” MMWR, 1993, 42 (RR-6), 1-14; Palache, A. M. et al. “Antibody response after influenza immunization with various vaccine doses: A double-blind, placebo-controlled, multi-centre, dose-response study in elderly nursing-home residents and young volunteers” Vaccine, 1993, 11, 3-9; Potter, C. W. “Inactivated influenza virus vaccine” In: Beare A S, ed. Basic and applied influenza research, Boca Raton, Fla.: CRC Press, 1982, 119-158).Paramyxoviridae        
The Paramyxoviridae is a group of negative single-stranded RNA viruses with a genome size from 16-20 kb. They are enveloped viruses of approximately 150-300 nm. An overview of the Paramyxoviridae taxonomy is available from the International Committee for Taxonomy of Viruses. The Paramyxoviridae consists of two subfamilies.                1. Paramyxovirinae. This subfamily contains three genera:                    a) Paramyxovirus. This genus is represented by Sendai virus and including human parainfluenza viruses 1 and 3;            b) Rubulavirus. This genus is represented by the mumps virus, simian virus 5, Newcastle disease virus and the human parainfluenza viruses 2 and 4;            c) Morbillivirus. This genus is represented by the measles virus; and                        2. Pneumovirinae. This subfamily encode a larger number of mRNAs than the other sub-family (ten, compared with six or seven) and contains only one genera:                    a) Pneumovirus. This genus is best represented by the respiratory syncytial virus (RSV), but also includes bovine (BRSV), ovine RSV (ORSC), caprine RSV (CRSV), pneumonia virus of mice (PVM) and turkey rhinotracheitis virus (TRTV).                        
One of the most important Pneumovirinae infections in humans is caused by the respiratory syncytial virus (RSV). RSV is the most important cause of viral lower respiratory tract disease in infants and children worldwide. In most areas, RSV outranks all other microbial pathogens as a cause of pneumonia and bronchiolitis in infants under one year of age. It has also been found that RSV infection is an important agent of disease in immunosuppressed adults and in the elderly. Additionally, BRSV has been shown to be an economically important disease in cattle.
The 3′-end of genomic RSV RNA consists of a 44-nucleotide extragenic leader region that is presumed to contain the major viral promoter. The leader region is followed by the ten viral genes, which is followed by a 155-nucleotide extragenic trailer region. Eighty eight percent of the genomic RNA is accounted for by the ORFs for the ten major proteins. Each gene begins with a conserved nine-nucleotide gene-start signal. For each gene, transcription begins at the first nucleotide of the signal. Each gene terminates with a semi-conserved 12 to 13 nucleotide gene-end signal that directs transcriptional termination and polyadenylation. The first nine genes are non-overlapping and are separated by intergenic regions that range in size from 1 to 52 nucleotides. The intergenic regions do not contain any conserved sequence motifs or any obvious features of secondary structure. The last two RSV genes overlap by 68 nucleotides. Thus, one of the gene-start signals is located inside of, rather than after the other gene.
Examples of antiviral agents that have been identified as active against RSV include:                1. Ribavirin (Hruska, J. F. et al. “In vivo inhibition of respiratory syncytial virus by ribavirin” Antimicrob Agents Chemother, 1982, 21, 125-130); and        2. Purified human intravenous IgG-IVIG (Prince, G. A. et al. “Effectiveness of topically administered neutralizing antibodies in experimental immunotherapy of respiratory syncytial virus infection in cotton rats” J Virol, 1987, 61, 1851-1954; Prince, G. A. et al. “Immunoprophylaxis and immunotherapy of respiratory syncytial virus infection in cotton rats” Infect Immun, 1982, 42, 81-87).Abnormal Cellular Proliferation        
Cellular differentiation, growth, function and death are regulated by a complex network of mechanisms at the molecular level in a multicellular organism. In the healthy animal or human, these mechanisms allow the cell to carry out its designed function and then die at a programmed rate.
Abnormal cellular proliferation, notably hyperproliferation, can occur as a result of a wide variety of factors, including genetic mutation, infection, exposure to toxins, autoimmune disorders, and benign or malignant tumor induction.
There are a number of skin disorders associated with cellular hyperproliferation. Psoriasis, for example, is a benign disease of human skin generally characterized by plaques covered by thickened scales. The disease is caused by increased proliferation of epidermal cells of unknown cause. In normal skin the time required for a cell to move from the basal layer to the upper granular layer is about five weeks. In psoriasis, this time is only 6 to 9 days, partially due to an increase in the number of proliferating cells and an increase in the proportion of cells which are dividing (G. Grove, Int. J. Dermatol. 18:111, 1979). Approximately 2% of the population in the United States have psoriasis, occurring in about 3% of Caucasian Americans, in about 1% of African Americans, and rarely in native Americans. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.
Other hyperproliferative cell disorders include blood vessel proliferation disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors and cancers.
Blood vessel proliferative disorders include angiogenic and vasculogenic disorders. Proliferation of smooth muscle cells in the course of development of plaques in vascular tissue cause, for example, restenosis, retinopathies and atherosclerosis. The advanced lesions of atherosclerosis result from an excessive inflammatory-proliferative response to an insult to the endothelium and smooth muscle of the artery wall (Ross, R. Nature, 1993, 362:801-809). Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.
Fibrotic disorders are often due to the abnormal formation of an extracellular matrix. Examples of fibrotic disorders include hepatic cirrhosis and mesangial proliferative cell disorders. Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar. Hepatic cirrhosis can cause diseases such as cirrhosis of the liver. An increased extracellular matrix resulting in a hepatic scar can also be caused by viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis.
Mesangial disorders are brought about by abnormal proliferation of mesangial cells. Mesangial hyperproliferative cell disorders include various human renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic micro-angiopathy syndromes, transplant rejection, and glomerulopathies.
Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease that is thought to be associated with activity of autoreactive T cells (See, e.g., Harris, E. D., Jr., The New England Journal of Medicine, 1990, 322: 1277-1289), and to be caused by autoantibodies produced against collagen and IgE.
Other disorders that can include an abnormal cellular proliferative component include Behcet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immune deficiency syndrome, vasculitis, lipid histiocytosis, septic shock and inflammation in general.
A tumor, also called a neoplasm, is a new growth of tissue in which the multiplication of cells is uncontrolled and progressive. A benign tumor is one that lacks the properties of invasion and metastasis and is usually surrounded by a fibrous capsule. A malignant tumor (i.e., cancer) is one that is capable of both invasion and metastasis. Malignant tumors also show a greater degree of anaplasia (i.e., loss of differentiation of cells and of their orientation to one another and to their axial framework) than benign tumors.
Approximately 1.2 million Americans are diagnosed with cancer each year, 8,000 of which are children. In addition, 500,000 Americans die from cancer each year in the United States alone. Prostate and lung cancers are the leading causes of death in men while breast and lung cancer are the leading causes of death in women. It is estimated that cancer-related costs account for about 10 percent of the total amount spent on disease treatment in the United States (CNN.Cancer.Factshttp://www.cnn.com/HEALTH/9511/conquer_cancer/facts/index.html, page 2 of 2, Jul. 18, 1999).
Proliferative disorders are currently treated by a variety of classes of compounds including alkylating agents, antimetabolites, natural products, enzymes, biological response modifiers, miscellaneous agents, radiopharmaceuticals (for example, Y-90 tagged to hormones or antibodies), hormones and antagonists, such as those listed below.
Alkylating Agents
Nitrogen Mustards: Mechlorethamine (Hodgkin's disease, non-Hodgkin's lymphomas), Cyclophosphamide, Ifosfamide (acute and chronic lymphocytic leukemias, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, neuroblastoma, breast, ovary, lung, Wilms' tumor, cervix, testis, soft-tissue sarcomas), Melphalan (L-sarcolysin) (multiple myeloma, breast, ovary), Chlorambucil (chronic lymphoctic leukemia, primary macroglobulinemia, Hodgkin's disease, non-Hodgkin's lymphomas).
Ethylenimines and Methylmelamines: Hexamethylmelamine (ovary), Thiotepa (bladder, breast, ovary).
Alkyl Sulfonates: Busulfan (chronic granuloytic leukemia).
Nitrosoureas: Carmustine (BCNU) (Hodgkin's disease, non-Hodgkin's lymphomas, primary brain tumors, multiple myeloma, malignant melanoma), Lomustine (CCNU) (Hodgkin's disease, non-Hodgkin's lymphomas, primary brain tumors, small-cell lung), Semustine (methyl-CCNU) (primary brain tumors, stomach, colon), Streptozocin (STR) (malignant pancreatic insulinoma, malignant carcinoin).
Triazenes: Dacarbazine (DTIC; dimethyltriazenoimidazole-carboxamide) (malignant melanoma, Hodgkin's disease, soft-tissue sarcomas).
Antimetabolites
Folic Acid Analogs: Methotrexate (amethopterin) (acute lymphocytic leukemia, choriocarcinoma, mycosis fungoides, breast, head and neck, lung, osteogenic sarcoma).
Pyrimidine Analogs: Fluorouracil (5-fluorouracil; 5-FU) Floxuridine (fluorodeoxyuridine; FUdR) (breast, colon, stomach, pancreas, ovary, head and neck, urinary bladder, premalignant skin lesions) (topical), Cytarabine (cytosine arabinoside) (acute granulocytic and acute lymphocytic leukemias).
Purine Analogs and Related Inhibitors: Mercaptopurine (6-mercaptopurine; 6-MP) (acute lymphocytic, acute granulocytic and chronic granulocytic leukemia), Thioguanine (6-thioguanine: TG) (acute granulocytic, acute lymphocytic and chronic granulocytic leukemia), Pentostatin (2′-deoxycyoformycin) (hairy cell leukemia, mycosis fungoides, chronic lymphocytic leukemia).
Vinca Alkaloids: Vinblastine (VLB) (Hodgkin's disease, non-Hodgkin's lymphomas, breast, testis), Vincristine (acute lymphocytic leukemia, neuroblastoma, Wilms' tumor, rhabdomyosarcoma, Hodgkin's disease, non-Hodgkin's lymphomas, small-cell lung).
Epipodophylotoxins: Etoposide (testis, small-cell lung and other lung, breast, Hodgkin's disease, non-Hodgkin's lymphomas, acute granulocytic leukemia, Kaposi's sarcoma), Teniposide (testis, small-cell lung and other lung, breast, Hodgkin's disease, non-Hodgkin's lymphomas, acute granulocytic leukemia, Kaposi's sarcoma).
Natural Products
Antibiotics: Dactinomycin (actinonmycin D) (choriocarcinoma, Wilms' tumor rhabdomyosarcoma, testis, Kaposi's sarcoma), Daunorubicin (daunomycin; rubidomycin) (acute granulocytic and acute lymphocytic leukemias), Doxorubicin (soft tissue, osteogenic, and other sarcomas; Hodgkin's disease, non-Hodgkin's lymphomas, acute leukemias, breast, genitourinary thyroid, lung, stomach, neuroblastoma), Bleomycin (testis, head and neck, skin and esophagus lung, and genitourinary tract, Hodgkin's disease, non-Hodgkin's lymphomas), Plicamycin (mithramycin) (testis, malignant hypercalcema), Mitomycin (mitomycin C) (stomach, cervix, colon, breast, pancreas, bladder, head and neck).
Enzymes: L-Asparaginase (acute lymphocytic leukemia).
Biological Response Modifiers: Interferon-alfa (hairy cell leukemia, Kaposi's sarcoma, melanoma, carcinoid, renal cell, ovary, bladder, non Hodgkin's lymphomas, mycosis fungoides, multiple myeloma, chronic granulocytic leukemia).
Miscellaneous Agents
Platinum Coordination Complexes: Cisplatin (cis-DDP) Carboplatin (testis, ovary, bladder, head and neck, lung, thyroid, cervix, endometrium, neuroblastoma, osteogenic sarcoma).
Anthracenedione: Mixtozantrone (acute granulocytic leukemia, breast).
Substituted Urea: Hydroxyurea (chronic granulocytic leukemia, polycythemia vera, essential thrombocytosis, malignant melanoma).
Methylhydrazine Derivative: Procarbazine (N-methylhydrazine, MIH) (Hodgkin's disease).
Adrenocortical Suppressant: Mitotane (o,p′-DDD) (adrenal cortex), Amino-glutethimide (breast).
Adrenorticosteriods: Prednisone (acute and chronic lymphocytic leukemias, non-Hodgkin's lymphomas, Hodgkin's disease, breast).
Progestins: Hydroxprogesterone caproate, Medroxyprogesterone acetate, Megestrol acetate (endometrium, breast).
Anti-Angiogenesis Agents
Angiostatin, Endostatin.
Hormones and Antagonists
Estrogens: Diethylstibestrol Ethinyl estradiol (breast, prostate)
Antiestrogen: Tamoxifen (breast).
Androgens: Testosterone propionate Fluxomyesterone (breast).
Antiandrogen: Flutamide (prostate).
Gonadotropin-Releasing Hormone Analog: Leuprolide (prostate).
Toxicity associated with therapy for abnormally proliferating cells, including cancer, is due in part to a lack of selectivity of the drug for diseased versus normal cells. To overcome this limitation, therapeutic strategies that increase the specificity and thus reduce the toxicity of drugs for the treatment of proliferative disorders are being explored. One such strategy that is being aggressively pursued is drug targeting.
In view of the severity of these diseases and their pervasiveness in animals, including humans, it is an object of the present invention to provide a compound, method and composition for the treatment of a host, including animals and especially humans, infected with any of the viruses described above, including flavivirus or pestivirus, influenza virus or Respiratory Syncytial Virus (“RSV”).
It is another object of the present invention to provide a method and composition for the treatment of a host, including animals and especially humans, with abnormal cellular proliferation.
It is a further object to provide a method and composition for the treatment of a host, including animals and especially humans, infected with hepatitis C or BVDV.
It is a further object to provide a method and composition for the treatment of a host, including animals and especially humans, infected with influenza.
It is a further object to provide a method and composition for the treatment of a host, including animals and especially humans, infected with RSV.
It is a further object to provide a method and composition for the treatment of a host, including animals and especially humans, with a tumor, including a malignant tumor.
It is yet another object of the present invention to provide a more effective process to quantify viral load, and in particular of BVDV or HCV load, in a host, including animals, especially humans.